It is believed that innovative adjuvants might be capable of inducing higher titers of broadly neutralizing anti-HIV-1 antibodies and better anti-HIV-1 T-cell responses. We propose to explore a novel opportunity to improve the effectiveness of anti-HIV vaccines by using anti-adenosinergic co-adjuvants. Our antiadenosinergic co-adjuvants are synthetic or natural antagonists of cAMP-elevating A2A adenosine receptor (A2AR). We hypothesize that these co-adjuvants will enhance anti-HIV immunity by preventing the inhibition of anti-HIV immune response by extracellular adenosine. This is because adenosine may inhibit the anti-HIV T- B- and myeloid cells by signaling via their A2AR. Together with Project 4, we will use our co-adjuvants to further improve the effects of unique bifunctional nanoparticle HIV immunogens (from Projects 1, 2) that display the natively-structured and lipid envelope-embedded HIV-1 MPER segment and release CD4 T cell epitopes from the particle core. The novel HIV immunogens, together with co-adjuvants, are expected to increase the contribution of T- and B-lymphocytes and myeloid cells to unleash their full anti-HIV capacities by preventing their inhibition by A2AR. In our aims, we will determine whether co-adjuvants will prevent inhibition of cells of innate and adaptive immune systems so they will fully express their anti-HIV vaccine-induced activities. We have already demonstrated the strong enhancement of anti-pathogen- and anti-tumor immunity by A2AR antagonists in several in vivo models of infectious diseases and cancer. In support ofthe feasibility ofthe studies proposed here, we show that treatment with synthetic or natural A2AR antagonists resulted in significantly increased levels of anti-HIV gpl20 IgGI, lgG2a and IgM in mice that have been vaccinated with HIV gpl20 plus adjuvant (Alum or MPLA). This method of co-adjuvanting to generate an order of magnitude augmentation of gp120-specific antibody can now be applied to immunogens eliciting broadly neutralizing antibodies.